Understanding the compaction behaviour of Low-substituted HPC: Macro, micro and nano-metric

evaluations

Authors: Amr ElShaer1,*, Ali Al-khattawi2, Afzal R. Mohammed2, Monika Warzecha3 , Dimitrios A.

Lamprou3,4 , Hany Hassanin5

1Drug Discovery, Delivery and Patient Care (DDDPC), School of Life Sciences, Pharmacy and

Chemistry, Kingston University London, Kingston-upon-Thames, Surrey, KT1 2EE, UK

2Aston Pharmacy School, Aston University, Aston Triangle, Birmingham B4 7ET, UK

3Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde, 161

Cathedral Street, Glasgow, G4 0RE, U.K.

4EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation,

University of Strathclyde, Technology and Innovation Centre, 99 George Street, Glasgow, G1 1RD,

U.K.

5School of Mechanical and Automotive Engineering, Kingston University London, Kingston Upon

Thames, Surrey, KT1 2EE, UK

* Corresponding author

Dr Amr ElShaer

Drug Discovery, Delivery and Patient Care (DDDPC)

School of Life Sciences, Pharmacy and Chemistry Kingston University London

Penrhyn Road, Kingston-upon-Thames,

Surrey, KT1 2EE, UK

Email: a.elshaer@kingston.ac.uk

T +44 (0)20 8417 7416 (Internal: 67416)

Abstract

The fast development in materials science has resulted in the emergence of new pharmaceutical

materials with superior physical and mechanical properties. Low-substituted hydroxypropyl cellulose

is an ether derivative of cellulose and is praised for its multi-functionality as a binder, disintegrant,

film coating agent and as a suitable material for medical dressings. Nevertheless, very little is known

about the compaction behaviour of this polymer. The aim of the current study was to evaluate the

compaction and disintegration behaviour of four grades of L-HPC namely; LH32, LH21, LH11 and

LHB1. The macrometric properties of the four powders were studied and the compaction behaviour

was evaluated using the out-of-die method. LH11 and LH22 showed poor flow properties as the

powders were dominated by fibrous particles with high aspect ratios, which reduced the powder

flow. LH32 showed a weak compressibility profile and demonstrated a large elastic region, making it

harder for this polymer to deform plastically. These findings are supported by AFM which revealed

the high roughness of LH32 powder (100.09±18.84 nm), resulting in small area of contact, but

promoting mechanical interlocking. On the contrary, LH21 and LH11 powders had smooth surfaces

which enabled larger contact area and higher adhesion forces of 21.01±11.35 nN and 9.50±5.78 nN

respectively. This promoted bond formation during compression as LH21 and LH11 powders had low

strength yield.

Keywords: L-HPC, Compaction, porosity, AFM, BET, disintegration time.

List of abbreviations

AFM Atomic force microscopy

BET Brunauer-Emmett-Teller

BJH Barrett–Joyner–Halenda

ε porosity

Dp poured density

Dt tapped density

L-HPC low-hydroxypropyl cellulose

g gram

LH-11 low-hydroxypropyl cellulose grade 11

LH-21 low-hydroxypropyl cellulose grade 21

LH-32 low-hydroxypropyl cellulose grade 32

LH-B1 low-hydroxypropyl cellulose grade B1

LH-41 low-hydroxypropyl cellulose grade 41

SEM scanning electron microscopy

MCC Microcrystalline cellulose

MP micropore

ρd bulk density

ρt true density

VMD volume mean diameter

s second

XRD X-ray powder diffractometry

1. Introduction

New pharmaceutical formulations continually emerge over the years, thanks to the fast

development of materials science and the introduction of new pharmaceutical excipients.

Understanding the physical and mechanical behaviour of pharmaceutical materials by evaluating

their micro and macrometrics will help in developing successful delivery systems. Some of the

pharmaceutical materials are of bio-based origin such as alginate, chitin-chitosan, poly lactic acid

and cellulose. Cellulose is a widely used excipient in tablet manufacturing, the bio-based material

was first isolated by a French Chemist in 1839 from plant matter (Purves., 1946). Nowadays,

between 1010-1011 tonnes of cellulose are produced annually to be used in chemical, material and

textile industries (Azizi Samir et al., 2005).

As a bio-based material, cellulose offers unique characteristics such as good biocompatibility, high

tensile strength, thermal stability and superior mechanical properties. Nonetheless, cellulose is

poorly soluble in most of the common solvents and lacks the thermoplastic properties desired.

Chemical and physical modifications of cellulose structure have been investigated (Roy et al., 2009;

Hebeish and Guthrie, 1981), primarily via esterification reactions with nitrate and acetic acid

derivatives (Klemm et al., 2005) and etherification with methyl, carboxy methyl and hydroxyalkyl

derivatives (Fox et al., 2011).

Low-substituted hydroxypropyl cellulose is an ether derivative of cellulose, where a low percentage

of hydroxyl groups (between 0.1 to 0.5%) in the repeating glucose units have been

‘hydroxypropylated’, forming –OCH2CH(OH)CH3 groups (Figure 1), using propylene oxide (Onda et al.,

1978). Unlike typical HPC polymers (with 2- 4.5% substitution per glucose unit), L-HPC is water

insoluble and commonly used as a binder and disintegrant in solid dosage forms (Shirai et al., 1994).

L-HPC is praised for its multi-functionality. Not only it can be used as binder, but also, due to its inert

nature, as a film coating agent for preparing floating systems (Diós et al., 2015) and in the

preparation of medical dressings (Ogawa et al., 2014). Besides, L-HPC has been used to improve drug

dissolution and oral bioavailability by forming dispersion systems with water insoluble drugs (Torre-

Iglesias et al., 2014).

Sustained drug release is a common application of L-HPC as it forms a gel-layer around the tablet

which then acts as a diffusion barrier. The water mobility and diffusion across L-HPC was evaluated

in a study using magnetic resonance imaging (MRI) (Kojima and Nakagami., 2002). The study

confirmed the formation of a gel-layer around the hydrated L-HPC tablet across which water

mobility diminished, suggesting a restricted diffusion of water in all the hydrated tablets. In addition,

LH41 was used in a series of studies by Kawashima et al (Kawashima et al., 1993)to control the

release of acetaminophen. The study documented that LH41 managed to prolong the

acetaminophen release at acidic pH for concentrations above 20%. On the other hand, substituting

LH41 with coarse L-HPCs such as LH21, LH31 and LH11 resulted in tablets with immediate drug

release because of the fast disintegration behaviour of these polymers. The discrepancies in the drug

release behaviour among the four polymers were attributed to low water uptake for LH41 tablets, in

addition to the formation of a continuous gel-layer across LH41 hydrated tablets (Kawashima et al.,

1993).

The use of L-HPC as a disintegrant was also evaluated in the literature (Ishikawa et al 2001; Sunada

and Bi 2002) and it is believed that L-HPC operates by a swelling disintegration mechanism due to

water gathering around the substituted hydroxypropyl (CH2CH(CH3)OH) groups, increasing the L-HPC

molecular size. Ishikawa and co-workers looked at formulating orally disintegrating tablets (ODTs)

using mixtures of L-HPC and MCC at different ratios. It was found that tablets prepared from a

mixture of MCC and L-HPC at a ratio of 9:1, had greater mechanical strength as well as fast

disintegration times. When the compression force of 1-6kN was applied, the ODTs were able to

withstand more than 3kg, indicating high hardness, but at the same time, underwent complete

disintegration in 15 sec. It is important to note that the amount of L-HPC used influenced the rate of

disintegration. Nevertheless, it was observed that by increasing the concentration of L-HPC to 40-

50% in the mixture, the disintegration time became longer. Though the extent of swelling action

mentioned above, which is utilised by the polymer is up 10 fold when compared to MCC, such a high

amount starts to disrupt the wetting ability required for disintegration. Usually by increasing the

concentration of L-HPC, the disintegration time decreased (Ishikawa et al., 2001).

Another study conducted by Sunada and Bi exhibited similar findings; the study attempted to

formulate ODTs using a mixture of MCC and L-HPC using direct compression and wet compression.

Wet granules were prepared and compressed at low compression forces prior to drying in circulating

air oven. It was observed that mechanical strength increased when the proportion of MCC to L-HPC

in the mixture increased. However, such mixtures also had reduced porosity. ODT containing a ratio

of 7:3 MCC :L-HPC was tested, and found to have tensile strength and porosity of 3 MPa and 0.08,

respectively. Whereas a 9:1 mixture had tensile strength and porosity of 3.6 MPa and 0.06,

respectively. It was observed that increasing tablets’ tensile strength was associated with a drop in

porosity and this was attributed to the ability of MCC to form a greater number of interactions using

the hydroxyl groups in its structure when it underwent direct compression (Sunada and Bi 2002).

The Ishikawa et al and Sunada and Bi studies demonstrated that L-HPC can achieve success in

manufacturing orally disintegrating tablets, maintaining the mechanical properties without

sacrificing a fast disintegration time.

Despite the fact that many polymers have been studied in the field of ODTs, L-HPC is one polymer

which has not been studied as extensively when compared to some of the polymers mentioned

above. The potential of L-HPC in ODTs has been claimed by its manufacturers. However, a survey of

the literature shows that very little is known about this polymer. Therefore, the focus of this study

was to evaluate the compaction and disintegrating behaviour of four L-HPC grades namely LH21,

LH32, LH11 and LHB1 (Table 1) during ODT manufacture. The nano, micro and macrometric

properties of the four polymers were evaluated in order to understand their compaction

mechanism.

Table 1: Summary of the properties of the four grades of L-HPC; LH31, LHB1, LH21 and LH11 reported by the manufacturer (Shin-Etsu).

L-HPC grade Average

molecular

weight

Hydroxypropyl

content %

Degree of

polymerisation

Characteristics

LH32 115,000 8 660 White, fine powder

LHB1 140,000 11 790 White, coarse

powder

LH21 120,000 11 680 White, coarse

powder

LH11 130,000 11 730 White, coarse

powder

2. Materials and methods

2.1. Materials

Low-substituted hydroxypropylcellulose grade LH21, Low-substituted hydroxypropylcellulose grade

LHB1, Low-substituted hydroxypropylcellulose grade LH11, Low-substituted hydroxypropylcellulose

grade LH32 all were gifted from Shin-Etsu Chemical Co. Ltd.(Chiyoda-Ku, Tokyo, Japan).

2.2. Methods 2.2.1. Particle size analysis

Volume-weighted particle size analysis of all individual polymers was conducted using a Sympatec

HELOS/RODOS (Clausthal-Zellerfeld, Germany) laser diffraction particle size analyser. The dispersion

of air pressure was adjusted to 2.0-bar and a feed rate of 20% was applied. The particle size

distributions (PSDs), i.e., particle size at 10% (D10%), 50% (D50%, median diameter), 90% (D90%) of the

volume distribution and volume mean diameter (VMD) (mean ± SD, n = 3), were all calculated

automatically using the WINDOX software based on Fraunhofer theory. Approximately 1 g of each

powder was hand-fed into the VIBRI RODOS disperser. A background measurement was taken as the

reference test. The measurements were set to trigger when the optical concentration (Copt) was

higher than 1.1% and to end when the Copt fell below 1% for 5 s. The time-base was 100 ms and the

obstruction was ~ 10-30%.

2.2.2. Powder flow properties

L-HPC powder compressibility was determined by using the Pharma Test (TD1, Hainburg, Germany)

mechanical tapping device and following the USP guidelines <616> method I, and ultimately working

out each grade’s Carr’s Index and Hausner ratio. The powder was weighed (50g) and poured into a

250 ml measuring cylinder. The poured volume was recorded. The machine was then set to tap 50

times per test cycle. The tapped volume was recorded, and the machine run again. Tapped volume

was again recorded, and the process repeated until a steady tapped volume was obtained. The

maximum number of taps delivered per powder was 300. The Carr’s Index for each powder was

calculated using equation (1):

𝐶𝑎𝑟𝑟′𝑠 𝐼𝑛𝑑𝑒𝑥 = ((𝐷𝑡−𝐷𝑝)

𝐷𝑡) × 100 [1]

The Hausner ratio was also calculated using the equation (2):

𝐻𝑎𝑢𝑠𝑛𝑒𝑟 𝑟𝑎𝑡𝑖𝑜 = 𝐷𝑡

𝐷𝑝 [2]

Where Dt is the tapped density and Dp is the poured density.

2.2.3. Scanning Electron Microscopy (SEM)

Zeiss scanning electron microscope (Evo50, Oxford instruments, Inca wave, UK) was used to study

the surface morphology and particle size of the four polymers. Fine powder samples were lightly

sprinkled on the carbon surfaces of universal specimen stubs and double coated with gold under low

vacuum for about 4 min in the presence of Argon gas, using a sputter coater (Polaron SC500, Polaron

Equipment, Watford, UK) at 20 mA. The particle surface morphology was captured and analysed

using smartSEM software.

2.2.4. Specific surface area analysis

Specific surface area of the four polymers was studied using N2 adsorption/desorption. Nitrogen

adsorption/desorption measurements were carried out at T=77 K with Belsorp-mini (BEL, Japan Inc).

The Specific surface area of samples were calculated according to Brunauer-Emmett-Teller (BET)

model. Barrett–Joyner–Halenda (BJH) and micropore (MP) methods were used to calculate the pore

size distribution of the HPC samples. Before the analysis, samples of about 50-100 mg were

degassed undervacuum (about 5 μm Hg) and at T=353 K for 2 h. For the measurement of the

samples, a program was used that collects about 50 data points (25 each for adsorption and

desorption) evenly distributed between P/P0=0 and P/P0~1.

The specific surface area (as) was calculated using BET graphs and equation 3.

𝑎 =𝑉𝑚

22414𝐿𝜏 [3]

Where L is Avogadro constant, Vm is the monolayer volume and t is the cross sectional area of the

adsorbate molecule

2.2.5. X-ray powder diffractometry analysis

The main crystalline compounds in the samples were identified by qualitative X-ray powder

diffractometry (XRD) using a Siemens D5000 X-ray powder diffractometer with the characteristic

copper radiation and a scintillation detector with diffracted intensity of λ = 0.1542 nm at 40 kV and

30 mA) was measured at 2θ ranging between 4° and 50°.

2.2.6. Karl Fisher analysis

Karl Fisher titration was carried out using a KF Automatic titrator (Metrohm 787 Titrino), Aqualine

Complete 2 as the KF reagent and anhydrous methanol as the solvent. Samples were opened under

a dry environment and dissolved in 3 ml of KF reagent, before re-injection back into the Karl Fischer

cell. All measurements were done in triplicate.

2.2.7. Atomic force microscopy study

Atomic force microscopy (AFM) data was collected using a Bruker Dimension Icon® Atomic Force

Microscope using QNM PeakForce Tapping® mode at room temperature and ambient humidity. In

PeakForce Tapping® mode the probe is oscillating way below its resonance frequency in a sinusoidal

motion touching the sample only for a short time and generating the force curve. The data can be

analysed separately to obtain information about material properties such as adhesion, modulus or

dissipation known as quantitative nanomechanical mapping (QNM). A Probe with 0.4 N/m nominal

spring constant and triangular Si3N4 tip was used (Scan Asyst Air, Bruker), with nominal tip radius of

2 nm. The spring constant was calibrated using a thermal-tune method. Deflection sensitivity was

calibrated using hard surface (Sapphire, Bruker) Sample immobilized on the metal puck using a

double tape. Due to fibrous morphology, small particles size and their random orientation the

immobilization of the particles was a significant challenge, hence AFM data were collected from two

particles from each sample with scan size of 5 μm, scan rate 1.5 Hz, sample/lines 512. Nanoscope

Analysis v1.5 software was used for image analysis. First order plane fit was applied to all height

sensor micrographs. Roughness data were obtained from height micrographs using ‘Roughness

function’ in Nanoscope analysis v1.5.

2.2.8. Tablet preparation

In order to evaluate the compressibility and tabletability of L-HPC powders, 500 mg of the powders

were accurately weighted out and directly compressed. The powders were directly compressed

using a uniaxial hydraulic press (Specac tablet presser, Kent, UK) and 13 mm split, in order to prevent

mechanical failure the decompression process was controlled using . Powders were compressed at

compression pressures 74, 148, 22, 295 and 443 MPa, with a dwell time of 30 sec. Cylindrical tablets

with diameter of ~13 mm and flat faced surface were obtained. A desiccator containing silicon

dioxide was used to maintain relative humidity under 4% (Ebro Data logger, EBI 20-IF, Germany), L-

HPC powders and tablets were stored under desiccation for at least 48 hours and at 25 oC prior to

use.

2.2.9. Tablets’ porosity measurements

Bulk densities of the prepared tablets were determined by using a digital calliper to measure the

dimensions of the pre-weighed tablets. The tablet true density was measured using a helium

pycnometer (Multipycnometer Quantachrome Instruments, Hampshire, UK). Both bulk and true

density values were used to determine the tablets’ porosity using equation 4.

)/1(100 td [4]

Where ε is the porosity and ρd is the bulk density and ρt is the true density of the polymer powder.

All the measurements were done in triplicate.

2.2.10. Tablet tensile strength measurement

The force required to crush the tablets was measured using a tablet hardness apparatus (Schleuniger

4M, Thun, Switzerland). The measured force was used to determine the tablet tensile strength using

equation 5.

dt

Fc

2 [5]

Where σ is the tablet tensile strength, Fc is the crushing force required to break the tablet, d is the

tablet diameter and t is the tablet thickness. All measurements were done in triplicate.

2.2.11. Heckel analysis

The Heckel equation (6) was used to analyse the tablet’s compression characteristics.

𝒍𝒏 (𝟏

𝟏−𝑫) = 𝑲𝑷 + 𝑨 [6]

Where D is the tablet relative density at pressure P, K is a material constant (slope of the straight line

portion of the Heckel plot) and is 1/3 of the yield strength. The 1/K value is used to express the mean

yield pressure and gives an indication of the material’s ability to undergo plastic deformation under

pressure. A is a function of the initial bulk volume and is calculated from the intercept of the straight

line of the Heckel plot. It provides information on the movement/rearrangement of particles at the

initial stages of compaction.

2.2.12. Young’s/Elastic modulus analysis

The elastic modulus was evaluated using texture profiling analysis (Texture Analyzer, TA.HDplus,

Stable Micro Systems, UK). The four polymers were compressed using a 6 mm diameter stainless

steel cylindrical flat bottomed probe which was connected to a 750 kgf cell and the powder was

compressed using high tolerance powder compaction rig with a compression die of 20 mm height

and 6 mm diameter. The samples were compressed to a maximum of 300 kgf with the probe moving

at test speed of 2 mm/s. A correlation between the stress (MPa) and strain (%) was established and

the Texture Exponent software was used to work out the gradient of the initial linear part of the

graph.

2.2.13. Disintegration time studies

In vitro disintegration time was evaluated using the US pharmacopoeia (35) monograph (<701>

disintegration). An Erweka ZT3, GMBH (Heusenstamm, Germany) was used in this study as the

disintegration apparatus and distilled water (800 ml) as the disintegration medium. The temperature

was thermostatically maintained at 37 °C. Three tablets were placed in the basket rack assembly and

covered with a transparent plastic disk. The disintegration time was taken as the time required for

tablets to disintegrate completely without leaving any bulk solid residue. All the measurements were

carried out in triplicate and presented as mean ± standard deviation.

2.2.14. Statistical analysis

All formulations were prepared and analysed in triplicate and the results were expressed as mean±

standard deviation. Minitab® (version 17.1.0) was used to statistically evaluate the date obtained;

the results were analysed using Mann-Whitney test.

Results and discussion

2.3. Powder flowability

Powder flow plays a crucial role in the numerous processes of pharmaceutical manufacturing,

including pellet, granules and tablet formation and capsule filling. Hence, good flowability is required

to ensure uniform and consistent feed from bulk storage containers into the feeder during the

manufacturing process. Looking at the tabletting process, a good flowability ensures uniformity of

the tablets’ contents. The flowability of the four HPC powders was assessed using the Hausner ratio

and Carr’s index. LH32 showed the highest flowability with a Carr’s index of 7.83, while LHB1 had

poor flow properties with a Carr’s index of 28.6 (Figure 2a).

2.3.1 Particle size analysis

In order to understand the flowability behaviour of L-HPC powders, the particle size of the four

powders was assessed using laser diffraction. Particle size analysis for the four grades of L-HPC is

summarized in figure (2b). The data showed that low substituted hydroxyl propyl cellulose of LH32

grade has the lowest particle size with a volume mean diameter of 31.36±0.08 µm. On the other

hand, all the other grades showed larger particle sizes with volume mean diameters between

55.12±0.09 to 59.45±0.09 µm. The study of the flow properties of the four powders, showed LH32 to

have the best flow properties, despite having the smallest particle size amongst all HPC grades.

Moreover, both LH21, LH11 showed different flow behaviour compared to LHB1 particles despite

sharing the same volume mean diameter. Particle size is not the only determinant of the flow

properties of pharmaceutical powders; the shape of the powder also plays an important role in the

powder flowability. Therefore, the morphology of the four grades was evaluated using SEM.

2.3.2. Scanning Electron Microscopy

SEM images showed that the majority of LH32 particles were small and circular in shape, with a

diameter of around 20 µm (Figure 3a). LH32 circular particles were mixed together with a small

population of long fibres and both had a rough solid surface. On the contrary, LH21 and LH11

powders, (Figures 3b and 3c respectively) were dominated by long fibres. Fibrous particles have high

aspect ratios, which are associated with higher static and dynamic friction, which in turn reduces the

mass flow and powder flowability as suggested by (Horio et al., 2014). This could explain the poor

flow properties of LH11 and LH21 as both samples were dominated by fibrous particles with high

aspect ratios. On the other hand, looking at the LHB1 particles under the microscope showed that

the sample was dominated by spherical particles with diameters of around 50 µm (Figure 3d).

Because of the high population of spherical particles with low aspect ratios and large particle size, it

was expected that LHB1 would have superior flow properties. Nonetheless, the flow data showed a

different trend. As reflected by the SEM results, the four polymers contained mixtures of circular and

fibrous particles and this explains the wide range of particle size distribution to represent the

smallest minor diameter to the largest major diameter of the L-HPC powders.

2.3.3. Moisture Content Analysis

The powder flow is affected primarily by two forces; friction and cohesion (Nokhodchi, 2005). In

addition to the particles’ shape and size, moisture content will affect the friction and cohesion

forces. For instance, high moisture content in pharmaceutical powders will increase the frictional

forces, by increasing the static coefficient of friction between the particles (Karimi et al., 2009). ,

Moisture, however, diminishes the effect of electrostatic charges between particles, and in addition

the water content generates solid bridges between particles. This increases the cohesion forces and

thus affects the powder flow (Amidon and Houghton, 1995). The moisture content of the four

powders was assessed using Karl Fisher analysis (Table 2). LH-32 showed the highest moisture

content of 3.02±0.27 (P<0.1), followed by LHB1 (2.52±0.17), then LH21 and LH11 (Table 2). In

general, moisture content is inversely proportional to the powder flow rate i.e. increasing the

moisture content of the powder will be associated with a decrease in the flow rate which means a

decrease in powder flowability (Crouter and Briens., 2014). The effect of adsorbed moisture on

powder behaviour becomes pronounced at moisture levels greater than 5%, as water acts as a

plasticizer and reduces the glass transition of the polymers, as seen in case of microcrystalline

cellulose (Sun C., 2007). All HPC powders showed low moisture content, which suggested that the

flow behaviour of these powders could not be explained on this basis. It could be concluded that the

LH21 and LH11 poor flow properties were attributed to the morphology of their particles. Their

fibrous structure and high aspect ratios reduced the flow properties. On the other hand, the

particles’ morphology, size and moisture content analysis failed to explain the flow behaviour of

LH32 and LHB1.

2.4. Powders compressibility profiles

The densification properties of the four L-HPC powders were studied by evaluating the changes in

the powders’ porosity at various compression pressures. Materials with superior compression

profiles are able to respond to high compression pressure by reducing their porosity, which could

play a role in increasing the contact surface area between particles, and enhance increasing particles

binding. Generally increasing the compression pressure was associated with decreasing the tablets’

porosity (Fig 4). LHB1 showed the highest compressibility profile with a porosity of (0.61±0.011) at a

compression pressure of 74 MPa (P<0.1), which reduced by around 0.10 at 295 MPa. This was

followed by LH21, LH32 then LH11. LH32 powders changed their porosity by 0.08 when increasing

the compression pressure by 369 MPa (i.e between 74 and 443 MPa).

Table 2: Summary of moisture content (%), yield pressure (MPa), yield strength and tensile strength at f σ0 or LH32, LH21, LH11 and LHB1, * (P<0.1).

Polymer grade Powder true density

Moisture content (%)

Yield Pressure (MPa) 1/k

Yield strength

Tensile strength at zero

Young’s Modulus (MPa)

(g/cm3) porosity (σ0)

LH32 2.67±0.04* 3.02±0.27* 2000 666.66 108.68 0.08±0.01*

LH11 2.57±0.04* 2.32±0.16 625 208.33 9171.50 0.37±0.02*

LH21 2.55±0.02* 2.32±0.18 434.78 144.92 1120.30 0.21±0.05*

LHB1 2.78±0.02* 2.52±0.17 769.23 256.41 5081.40 0.64±0.11*

Table (2) summarizes the yield strength and yield pressure of the four powders. The Heckel analysis

(Figure 4) revealed that LH21 powder had the highest plasticity amongst the four L-HPC grades,

followed by LH11 and LHB1.

The stress/strain profiles revealed that LH32 powder has elastic properties and is more flexible than

the rest of the powders as reflected by its low Young’s modulus (0.08±0.01) Table (2). This means

that LH32 tends to reversibly deform and change its shape considerably under mechanical loading.

Besides, LH32 showed a high yield pressure of (2000 MPa), which suggests the need of high

compression pressure to permanently deform the material to move from the elastic region to the

plastic region of LH32 for an irreversible deformation. Moreover, pharmaceutical materials with high

elastic region yield strength are typically associated with manufacturing complications such as

capping, lamination and tablet breakage. This suggests that some issues could be associated with

compressing LH32 powder.

The formation of strong compacts during densification also known as compactability was studied for

the four L-HPC grades. Figure (6) shows that the tensile strength of LH11 and LHB1 decreases

exponentially decrease with increasing of porosity. All the four polymers showed a strong

exponential correlation with correlation coefficient ranging between 0.94 and 0.96. The

compactability profile of each powder was evaluated by calculating the tensile strength at zero

porosity (σ0) using the Ryshkewitch equation. σ0 was found to be 9171.50 MPa and 5081.40 MPa

for LH11 and LHB1 respectively. The high σ0 of LH11 and LHB1 suggested strong bond formation

between particles during the densification of the polymers’ powders. The formation of a compact or

tablet of a specific strength under compaction pressure is known as tabletability. Both

compressibility and compactabiltiy play a role in the tabletability. Powders with high compressibility

possess lower porosity under compression and are expected to have a higher inter-particulate

bonding area. While high compactability reflects the ability of the powder to form strong bonds

under compression. Both the large surface area and strong bond formation are necessary form good

tabletability. Figure (7) shows the tabletability profile of the four polymers. LH32 showed the highest

tensile strength at all compression pressures. The polymer had a tensile strength of 5.21 MPa at 74

MPa that increased to 8.32 MPa at 443 MPa. Nonetheless, the tensile strength remained steady

between 148 and 295 MPa. This could be attributed to the poor compressibility of LH32, as

demonstrated in Figure (5). On the other hand, LHB1 showed the lowest tabletability profile with a

mean tensile strength of 0.81 at 74 which steadily increased to 3.00 MPa at the maximum applied

compression pressure. LH32 tabletability was high despite having a weaker compressibility and

poorer plastic properties. The poor tabletability of LHB1 could be associated with a failure in the

bond formation of the polymer’s particles. In order to have a better understanding of the behaviour

of LH32 and LHB1, specific surface area analysis was conducted using the Brunauer-Emmett-Teller

method. Nitrogen adsorption and desorption isotherms and t-plots are summarized in Figure (8

a&b). All the four polymers showed adsorption/desorption isotherms of type III, revealing a weak

interaction between the L-HPC polymers and the adsorbate; moreover, type III isotherms reflect the

nonporous structure of the polymers. BET analysis showed that LH32 had the largest pore volume

(1.4x10-2 cm3) and the highest specific surface area (1.47 m2/g). The high surface area could be

attributed to the high content of small particles in the LH32 sample as suggested by the SEM images.

On the other hand, LHB1 had the lowest specific surface area of (0.24 m2/g). The high tabletability

behaviour of LH32 could be attributed to the high specific surface area as suggested earlier by

Paluch et al (Paluch et al., 2013). Paluch and co-workers concluded that a materials’ specific surface

area had a direct impact on powders’ tabletability, as it was observed that materials with large

specific surface area could compact well even at low compression pressure. A similar trend was

observed for LH32, with its tablets having a tensile strength of 5.21 MPa at 74 MPa compared to a

tensile strength of 0.81 MPa for LHB1 at the same compression pressure. Fibrous samples such as

LH21 and LH11 showed lower specific surface areas of 0.84 and 0.91 respectively.

Moisture content of pharmaceutical samples is another factor that is believed to play a significant

role in powder compaction, as water exhibits plasticizing effects (Sun 2008; Nokhodchi 2005). In this

study, the effect of moisture would be minimal as the moisture content was low and the difference

between LH21, LH11 and LHB1 polymers was insignificant (P>0.1) (Table 2). On the other hand, LH32

had a significantly higher moisture content of 3.02±0.27 compared to LH11 and LH21 (P>0.1) and

this might have played a role in increasing the tabletability of LH32.

Table 3: BET (Brunauer-Emmett-Teller) surface area, Mean pore diameter, #Total pore volume at

relative pressure (P/P0 = 0.97). *P<0.1.

Material BET specific surface area (m2/g)

t plot total specific area (m2/g)

Total pore volume# (cm3)

Roughness (nm) Adhesion force nN)

LH32 1.47 1.5 1.4x10-2 100.09±18.84 5.91 ± 1.63

LH11 0.91 0.87 6.08x10-3 2.43±1.41 * 9.50±5.78

LH21 0.84 0.85 5.5x10-3 9.07±14.42 * 21.01±11.35

LHB1 0.24 0.24 7.8x10-3 21.18±13.19 5.33 ± 3.61

It is also believed that crystal structure and orientation within pharmaceutical powder will have an

impact on the macroscopic properties of the material. X-ray diffraction of the L-HPC polymers was

investigated and data is summarised in Figure (9). XRD analysis did not reveal any sharp reflections

and all the L-HPC samples exhibited a large diffuse halo at 2ϴ between 15o -25o. This halo reflected

the amorphous features of the four L-HPC grades and is believed to play a role in the swallowing

behaviour of HPC polymers (Yamamoto et al. 2010; Palmeiro-Roldán et al., 2014). Because of the

similarity in the XRD profiles, it was strongly believed that the crystal structure of L-HPC polymers

had no effect on their compaction behaviour.

Surface roughness (Ra) is another factor that could be of particular importance in tablet formation as

it was reported that surface roughness affected the contact area between particles depending on

the size and distribution of asperities on the surface (Cooper et al., 2001; Beach et al., 2002). Atomic

force microscopy (AFM) can provide useful information about particles properties such as perimeter,

height and surface roughness, by providing a three-dimensional image at a vertical resolution of sub-

nanometer scale and lateral resolution of a few nanometers (Figures 11).

AFM data showed that LH32 particles had the highest surface roughness of 100.09±18.84 nm (P< 0.1

compared to LHB1). The high surface roughness could also explain the large specific surface area of

LH32 as revealed by BET studies and reported previously by Katsikogianni and Missirlis and Anitha et

al (Katsikogianni and Missirlis; Anitha et al., 2016). Nonetheless, increasing surface roughness is

associated with lower contact area, as the particles will contact at the tips only (Figure 12), hence

the low adhesion forces between LH32 particles (5.91 ± 1.63 nN). The AFM data revealed that

decreasing the surface roughness was associated with an increase in the adhesion forces (Figure 11),

which came in line with Cheng et al’s (Cheng et al, 2002) studies. In particular, particles with

smoother surfaces would have a larger area of contact with one another and higher chances of bond

formation, hence stronger adhesion forces. LH32 particles have large surface roughness and it is

believed that LH32 particles bind through mechanical interlocking and this could explain the superior

tensile strength of LH32 powder as suggested by Moon and Jang (Moon and Jang, 1999). On the

other hand, LH21 particles showed strong adhesion forces between particles (21.01± 11.35 nN),

which came in line with Heckel’s analysis, suggesting that LH21 powder compacted by plastic

deformation. A similar trend was observed for LH11, which exhibited an adhesion force of 9.50±5.78

nN.

Disintegration studies of the compacted tablets were evaluated and summarized in Figure (13). LHB1

tablets disintegrated within 150.67±4.04 s at low compression pressure and the disintegration time

increased to 573.67±20.3 s at 443 MPa (P< 0.1 vs LH32). On the other hand, LH32 tablets only

managed to disintegrate at 74 MPa and failed to break down when the compression pressure

increased above 74 MPa. This could be attributed to the low porosity of LH32 tablets as reported

earlier under the compressibility section. LH32 tablets had a porosity of 0.22±0.01 at 74 MPa which

dropped further upon increasing the compression pressure. The low porosity hindered water

permeation across the tablets and delayed the disintegration. Similar trends were observed in

studies carried out by Alvarez-Lorenzo (Alvarez-Lorenzo, 2000). Moreover, it had been reported that

the swelling rate and swelling work (swelling force) and the speed of water penetration affected the

rate of tablet disintegration. Upon swelling of the polymer a pressure was generated resulting in

disintegration of the tablets. Kawashima et al (Kawashima et al, 1993) reported that the swelling

rate and swelling work were affected by the particle size of L-HPC polymers. Studies showed that

fine particles had less ability to uptake water and did not swell as quickly as HPC polymers with large

particle size. LHB1 was reported to reach 100% swelling within less than 50 seconds followed by

LH11, LH21, then polymers with fine particles such as LH31 (Shin-Etsu). This explained the fast

disintegration of LHB1 tablets and the long disintegration time for LH32, which had a mean volume

diameter of 31.36±0.08 µm. Besides, the content of hydroxypropoxy (HPO) was believed to play a

role in the swelling abilities of L-HPC polymers, as L-HPC polymers with low HPO content such as

LH32 swell less than polymers with high HPO content.

3. Conclusion

The macro and micrometric properties of L-HPC polymers affect their compaction and disintegration

behaviour. LH32 powder showed a large specific surface area due to its small particle size and rough

surface. Nonetheless, under compression the polymer is believed to compress by mechanical

interlocking rather than plastic deformation, as the rough surface of the LH32 powder mediates and

enhances the mechanical interlocking during compression. On the other hand, L-HPC polymers with

smooth surfaces such as LH21 and LH11 are believed to have larger areas of contact, which

enhances adhesion. Together with the small elastic region, LH21 and LH11 compress via plastic

deformation. Among the four powders, only LHB1 demonstrated superior disintegration behaviour

and can be successfully used in preparing ODTs with both good mechanical strength and fast

disintegration time.

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Figure 1: Chemical structure of hydroxypropylcellulose

Figure 2: Hausner ratio and Carr’s index of the LH32, LH21, LH11 and LHB1 polymers (a) and laser diffraction particle size analysis using (b).

Figure 3: SEM images of LH32 (a), LH21 (b), LH11 (c) and LHB1 (d)

Figure 4:- Heckel plot showing the correlation between – lnporosity and the compaction pressure (MPa) for LH11, LH21. LH32 and LHB1.

Figure 5: Compressibility profiles showing the correlation between mean porosity of LH32, LH21, LH11 and LHB1 tablets at various compression pressures.

Figure 6: Compactability profiles showing the correlation between mean tensile strength (N/mm2) of LH32, LH21, LH11 and LHB1 tablets at various porosities.

Figure 7:- Tabilitability profiles showing the correlation between mean tensile strength (N/mm2) of LH32, LH21, LH11 and LHB1 tablets at various compression pressure.

Figure 8: showing the adsorption/desorption isotherm (a) and t-plot (b) for LH32 (A), LHB1 (B), LH11 (C), LH21 (D) where Va is the specific amount adsorbed expressed in the gas volume at standard state (STP T=273.15 K, 101.3 kPa) on 1 g of sample, P/P0 is the relative pressure and t is the adsorption layer thickness.

Figure 9: XRD diffraction pattern for LHB1 (A), LH32 (B), LH21 (C), LH11(D)

A

B

C

D

Figure 10: Peak force error, height micrograph and adhesion maps for LH11 (a), LHB1 (b). LH21 (c), LH32 (d).

Figure 11: Peak force error, height micrograph and adhesion maps for LH21 (a), LH32 (b).

Figure 12: Schematic presentation demonstrating the effect of surface roughness on the contact surface area.

Figure 13: Disintegration times in seconds for LH32, LH21, LH11 and LHB1 tablets.